Improving early prostate cancer (PCa) detection in African-American (AA) men is fundamental for reducing racial disparities in PCa mortality. PCa detection and management relies mainly on PSA screening. While the use of this test has improved the eariy diagnosis and management of PCa, its limitations in regards to specificity, particularly among obese AA men, demands complementary non-invasive approaches for enhancing early PCa detection, monitoring disease progression, and evaluating therapeutic responses. The implementation of these novel approaches will depend on the identification of more specific and sensitive biomarkers that could be tailored to AA men. We will use an immunoseroproteomics approach focused on profiling serum auto-antibodies to tumor-associated antigens (TAAs) and serum exosomes in AA and Caucasian (CC) PCa patients. The project fills the gap of the lack of systematic immunoseroproteomics studies for biomarker identification in AA patients with PCa. It builds on our key observations indicating that: 1) PCa sera contain auto-antibodies to TAAs involved in tumor stress survival such as LEDGF/p75 and Survivin, and could act as sensors of inflammation and an augmented state of cellular oxidative stress (ASCOS); 2) TAA mini-arrays enhance antibody detection in PCa patients and distinguish between cancer and normal populations; 3) customized mini-arrays of PCa-specific TAAs are most effective in enhancing immunoserological diagnosis of PCa; 4) PCa patient sera have exosomes that contain stress survival proteins such Survivin and PRDX3; and 5) there might be ethnic differences in the protein profiles or levels of serum exosomes. Our central hypothesis is that proteomic profiling of serum anti-TAA antibodies and exosomes in AA and CC PCa patients will yield novel biomarkers for enhancing early PCa detection and management, leading to the implementation of evidence-based interventions tailored to AA men. The aims are to: 1) profile anfi-TAA antibodies in sera from AA and CC PCa patients using immunoproteomics and customized TAA mini-arrays; 2) profile tumor-derived exosomal proteins in sera from AA and CC PCa patients by proteomics approaches; and 3) To determine in a comparative case-controlled pilot study if young AA men with no PCa diagnosis have increased serum levels of anti-TAA autoantibodies and tumorderived exosomal proteins, compared to AA men with PCa. Our goal is to identify and validate novel serum biomarkers that could be tailored to AA men to enhance the serological diagnosis of PCa, monitor disease progression, and guide personalized therapies.